Medication Presentation

1. Medication Presentation Torry A. Hansen

2. Glyburide • Generic name: Glyburide • Brand name:Micronase • Other brand names: DiaBeta, Glynase • Classifications: • Therapeutic: Antidiabetics • Pharmacologic: Sulfonylureas • Pregnancy Category B

3. Description • Glyburide is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound. , The chemical name for glyburide is:1-[ [p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 493.99. The structural formula is represented below.

4. Glyburide • Indications (Pharmacia & Upjohn, 2005): Glyburide tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. Glyburide may be used concomitantly with metformin when diet and glyburide or diet and metformin alone do not result in adequate glycemic control.

5. Actions/Uses • Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established.Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

6. Glyburide • Pharmacokinetics/Pharmacodynamics (Pharmacia & Upjohn, 2005): Single dose studies with glyburide in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

7. Glyburide Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic- binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug- drug interactions with glyburide.

8. Contraindications: Glyburide is contraindicated in patients with: 1. Known hypersensitivity or allergy to the drug. 2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. 3. Type I diabetes mellitus, as sole therapy. The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin (Herfindal & Gorley, 2003).

9. Interactions Glyburide may interact with the following (Deglin & Vallerand, 2005):

10. Common Side Effects: • Hypoglycemia • Gastrointestinal Reactions: Cholestatic jaundice, hepatitis, liver function abnormalities. Gastrointestinal disturbances, (eg, nausea, epigastric fullness, and heartburn are the most common). • Dermatologic Reactions: Allergic skin reactions, (eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions), Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. • Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

11. Common Side Effects • Metabolic Reactions (Pharmacia & Upjohn, 2005): Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. • Other Reactions (Pharmacia & Upjohn, 2005): Changes in accommodation and/or blurred vision have been reported with glyburide. These are thought to be related to fluctuation in glucose levels. In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.

12. Common dosages & frequency • There is no fixed dosage regimen for the management of diabetes mellitus with glyburide or any other hypoglycemic agent. • The usual starting dose of glyburide is 2.5 to 5 mg daily, administered with breakfast or the first main meal. • Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. • Transfer of patients from other oral antidiabetic regimens to glyburide should be done conservatively and the initial daily dose should be 2.5 to 5 mg (Pharmacia & Upjohn, 2005).

13. Common dosages & frequency Maximum Dose Daily doses of more than 20 mg are not recommended. Dosage Interval Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage. HOW SUPPLIED 1.25 mg Tablets 2.5 mg Tablets 5 mg Tablets

14. Specifics of taking/administration of medication • In diabetic subjects, there is no fixed dosage regimen for management of blood glucose levels. Individual determination of the minimum dose that will lower the blood glucose adequately should be made. If the maximal recommended dose fails to lower blood glucose adequately in patients on initial trial, glyburide should be discontinued. During the course of therapy a loss of effectiveness may occur. It is advisable to ascertain the contribution of the drug in the control of blood glucose by discontinuing the medication semi-annually or at least annually with careful monitoring of the patient (Pharmacia & Upjohn, 2005). • Glyburide is usually administered with breakfast or the first main meal. Do not administer after the last meal of the day. • Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit an unsatisfactory response to therapy.

15. Monitoring • In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose lowering response after an initial period of effectiveness. • Glycosylated hemoglobin levels may be of value in monitoring the patient’s response to therapy. • The CBC should also be monitored periodically throughout therapy.

16. Prescribing Implications • Glyburide is not recommended for use in pregnancy or for use in pediatric patients. • In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. • Adjustment of glyburide dosage should be considered whenever factors predisposing the patient to the development of hypo- or hyperglycemia, such as weight, life-style changes, stress, or infection are present. • Half-life—10 hr.

17. Glyburide • Dietary/drug restrictions (Deglin & Vallerand, 2005): • Restrict all drugs previously mentioned that are known to interact with glyburide. • Ingestion of alcohol may result in a disulfiram-like reaction. • Glucosamine may worsen blood glucose control. • Fenugreek, chromium, and coenzyme Q-10 may produce additive hypoglycemic effects. • Suggest a daily intake of no more than 10%-20% protein, 10%-20% from fat (less than 10% saturated), and 60%-70% from carbohydrates.

18. Glyburide • Storage Store at controlled room temperature 20 degrees to 25 degrees C (68 degrees to 77 degrees F). Dispense in well closed containers with safety closures. Keep container tightly closed.

19. Glyburide • Other items specific to this medication This drug may cause an increase in AST, LDH, BUN, and serum creatinine levels. Overdose of sulfonylureas can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the nurse practitioner is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery (Pharmacia & Upjohn, 2005).

20. Glyburide—Clinical Research • Describe and discuss the type of clinical research conducted using this drug (Pharmacia & Upjohn, 2005): • In a single dose interaction study with metformin, NIDDM subjects had decreases in glyburide AUC and Cmax. Results also demonstrated that coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. • An animal study was undertaken utilizing rats. These rats were given doses of up to 300 mg/kg/day of glyburide for 18 months. Results showed that glyburide was nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. Researchers concluded that there were no drug related carcinogenic effects in any of the criteria evaluated in this oncogenicity study.

21. Glyburide—Clinical Research • Reproduction studies have been performed in rabbits and rats at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, glyburide should be used during pregnancy only if clearly needed. • The University Group Diabetes Program (UGDP) conducted a randomized, long-term prospective study. The study was designed to evaluate the effectiveness of glucose lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 ½ times that of patients treated with diet alone. It is important to note that only one drug in the sulfonylurea class (tolbutamide) was included in this study. However, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class (such as glyburide), in view of their close similarities in mode of action and chemical structure.

22. Glyburide—Additional Research • A double-blind, randomized crossover study was conducted using 16 healthy volunteers. The objective of this study was to investigate the impact of glyburide on glucose counterregulatory hormones during stepwise hypoglycemic clamp studies. Researchers concluded that glyburide induces multiple defects in glucose counterregulatory hormonal responses, notably decreases in both glucagon and GH release (Van Haeften, 2002). • Langer, et. al. (2000) conducted a randomized, non-blinded, active-controlled study involving 404 gestational diabetic women with single fetus pregnancies. These women were randomly assigned to receive either glyburide or human insulin between 11 and 33 weeks of gestation. Achievement of desired glucose control was the primary endpoint. Maternal and neonatal complications were secondary endpoints. From their findings researchers concluded that glyburide is a safe and effective alternative to insulin in women with gestational diabetes. • A randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. The researchers concluded that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide (Hollander, et. al., 2001).

23. Objective data about the patient that the prescriber needs • Confirmation that the patient is diabetic (i.e. blood glucose levels). • Knowledge concerning whether the patient has (or has ever had) kidney or liver disease. • Assessment data that excludes adrenal or pituitary insufficiency. • For females, confirmation that patient is not pregnant, planning to become pregnant, or breastfeeding.

24. Patient Teaching • Educate the patient on glyburide, potential side effects and drug interactions. • Educate on the pathophysiology of Type II diabetes. • Educate on the importance of monitoring blood sugar levels. • If the patient is having surgery, including dental surgery, instruct him/her to tell the doctor or dentist that they are taking glyburide. • Tell the patient that this drug may make them drowsy. Advise him/her to not drive a car or operate machinery until they know how the drug affects them. • Inform the patient that alcohol can add to the drowsiness caused by this drug.

25. Patient Teaching Points • Cigarette smoking may decrease the effectiveness of glyburide. • Glyburide may make skin sensitive to sunlight. Plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. • Diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. • The importance of regular physical activity should be emphasized. • Emphasize the importance of yearly podiatric and opthalmologic exams. • Educate on the need for regularly scheduled lab studies and the importance of keeping all regularly scheduled follow-up appointments (American Society of Health-System Pharmacists, 2004).

26. Monitoring that should be implemented with this drug • Patients need to be monitored closely for adverse reactions. • Periodic assessment of cardiovascular, ophthalmic, hematologic, renal and hepatic status is advisable. • Routine laboratory tests that should be performed include: • CBC • Urinary glucose • Blood glucose • Glycosylated hemoglobin levels The effectiveness of any hypoglycemic drug including glyburide, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, (to distinguish it from primary failure in which the drug is ineffective when first given). Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure (Pharmacia & Upjohn, 2005).

27. Sample prescription Quality Health Care Torry Ann Hansen FNP 1234 Main Street Hermitage, TN 37076 Patient Name Jane Jacobs Date 11-05-05 Allergies None Indication: Type II Diabetes Rx Glyburide 2.5 mg PO qd (every day) Quantity: 32 (thirty-two) Refill 0 (zero) times Torry Ann Hansen FNP

28. References American Society of Health-System Pharmacists. (2004). Glyburide. Retrieved October 29, 2005 from, http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/storage-conditions Deglin, J.H., & Vallerand, A.H. (2005). Davis’s Drug Guide For Nurses. 9th Ed. Philadelphia. F.A. Davis. Herfindal, E. T., & Gorley, D. R. (2003). Textbook of therapeutics: Drug and disease management (7th Ed.). Philadelphia: Lippincott Williams & Wilkins. Hollander, P.A, Schwartz, S.L., Gatlin, M.R., Haas, S.J.,, Zheng, H., Foley, J.E., & Dunning, B.E. (2001). Comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 24:983-988. Langer, O.D, Conway D.L., Berkus, M.D., Xenakis, E.M.J, & Gonzales, O. (2000). A comparison of glyburide and insulin in women with gestational diabetes. New England Journal of Medicine, 343:1134-38. Pharmacia & Upjohn. (2005). Micronase. Retrieved October 28, 2005 from, http://66.218.69.11/search/cache?p=micronase&sm=Yahoo%21+Search&toggle=1&ei=UTF- 8&u=www.pfizer.com/download/uspi_micronase.pdf&w=micronase&d=TXydx2FULdKb&icp=1&.intl=us Van Haeften. T.W. (2002). The sulfonylurea glyburide induces impairment of glucagon and growth hormone responses during mild Insulin-Induced hypoglycemia. Retrieved October 29, 2005 from, http://www.highbeam.com/library/docfree.asp?DOCID=1G1:82270374&ctrlInfo=Round18%3AMode 18 c%3ADocG%3AResult&ao=